Adenosine A1 agonists and processes for their preparation are described in: EP0322242, WO97/43300, WO99/24449, WO99/24450, WO99/24452, WO99/67262, WO98/16539 (Novo Nordisk A/S); WO98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.); and WO98/01459 (Novo Nordisk A/S). For example, in WO99/67262 (Glaxo Group Limited), adenosine derivatives are prepared by reaction of a halopurine ribofuranose nucleoside with an amine either in the absence or presence of a solvent such as an alcohol, an ether, a substituted amide, a halogenated hydrocarbon, an aromatic hydrocarbon, dimethyl sulfoxide (DMSO) or acetonitrile, preferably at an elevated temperature, in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium, cesium or potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine or pyridine, optionally in the presence of a palladium catalyst and phosphine ligand.
An alternative process for the preparation of arylamines is described in U.S. Pat. No. 5,576,460 (Buchwald). This process involves reacting an amine with an aryl halide compound in the presence of a nickel or palladium catalyst. The present inventors found, however, that when reacting 6-halopurine ribofuranose nucleosides with certain amines (e.g. 4-chloro-2-fluoroaniline), the process had low reproducibility and tended to give incomplete reaction and very low yield. The incomplete reaction, in addition to the necessity of removing the palladium heavy metal makes the process impractical for preparing certain 6-substituted aminopurine ribofuranose nucleosides.
CaCO3 processes for preparing adenosine derivatives are described in Kwatra et al., (1987) J. Med. Chem. 30:954, Fleysher et al., (1969) J. Med. Chem. 12:1056 and Yadava et al. (1988) Himalayan Chem. Pharm Bull. 5:31. For example, Fleysher et al. describes the synthesis of N6-phenyladenosine from 6-chloropurine riboside in absolute ethanol in the presence of CaCO3. However, the present inventors found that when anilines of poor nucleophilicity like 4-cholor-2-fluoroaniline were reacted with 6-chloropurine riboside under these conditions, the reaction was slow and a significant amount of N6-aryladenine by-product was derived from cleavage of the glycosyl linkage. The reaction was also found to be sensitive to the choice of solvents, for example, it had no meaningful conversion in 2-methoxyethanol and provided only 25% yield of product in isopropanol.
The problem to be solved by the present invention was therefore to provide an improved process for the preparation of N6-substituted aminopurine ribofuranose nucleosides.